Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Cardiovasc Res. 2024 Mar 14;120(3):301-317. doi: 10.1093/cvr/cvae004.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced cardiac dysfunction is lacking. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic drugs that recently showed beneficial cardiovascular outcomes in patients with acquired forms of heart failure. We here studied if SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by an HCM sarcomere mutation.
Contractility was measured of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harbouring an HCM mutation cultured in 2D and in 3D engineered heart tissue (EHT). Mutations in the gene encoding β-myosin heavy chain (MYH7-R403Q) or cardiac troponin T (TNNT2-R92Q) were investigated. In 2D, intracellular [Ca2+], action potential and ion currents were determined. HCM mutations in hiPSC-CMs impaired relaxation or increased force, mimicking early features observed in human HCM. SGLT2i enhance the relaxation of hiPSC-CMs, to a larger extent in HCM compared to control hiPSC-CMs. Moreover, SGLT2i-effects on relaxation in R403Q EHT increased with culture duration, i.e. hiPSC-CMs maturation. Canagliflozin's effects on relaxation were more pronounced than empagliflozin and dapagliflozin. SGLT2i acutely altered Ca2+ handling in HCM hiPSC-CMs. Analyses of SGLT2i-mediated mechanisms that may underlie enhanced relaxation in mutant hiPSC-CMs excluded SGLT2, Na+/H+ exchanger, peak and late Nav1.5 currents, and L-type Ca2+ current, but indicate an important role for the Na+/Ca2+ exchanger. Indeed, electrophysiological measurements in mutant hiPSC-CM indicate that SGLT2i altered Na+/Ca2+ exchange current.
SGLT2i (canagliflozin > dapagliflozin > empagliflozin) acutely enhance relaxation in human EHT, especially in HCM and upon prolonged culture. SGLT2i may represent a potential therapy to correct early cardiac dysfunction in HCM.
肥厚型心肌病（HCM）是最常见的遗传性心肌病，通常由肌节致病性突变引起。HCM 的早期特征是舒张功能障碍和高收缩性。目前缺乏预防突变诱导的心脏功能障碍的治疗方法。钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2i）是一组抗糖尿病药物，最近在患有获得性心力衰竭的患者中显示出有益的心血管结局。我们在此研究 SGLT2i 是否代表一种纠正由 HCM 肌节突变引起的心肌细胞功能障碍的潜在治疗方法。
在二维和三维工程心脏组织（EHT）中培养携带 HCM 突变的人诱导多能干细胞衍生的心肌细胞（hiPSC-CM），测量收缩力。研究了编码β肌球蛋白重链（MYH7-R403Q）或肌钙蛋白 T（TNNT2-R92Q）的基因突变。在二维中，测定细胞内[Ca2+]、动作电位和离子电流。hiPSC-CM 中的 HCM 突变会损害舒张或增加力，模拟人类 HCM 中观察到的早期特征。SGLT2i 增强 hiPSC-CM 的舒张，在 HCM 中比对照 hiPSC-CM 增强更多。此外，SGLT2i 对 R403Q EHT 舒张的影响随培养时间（即 hiPSC-CM 成熟）而增加。坎格列净对舒张的作用比恩格列净和达格列净更明显。SGLT2i 急性改变 HCM hiPSC-CM 中的 Ca2+处理。分析 SGLT2i 介导的机制，这些机制可能是突变 hiPSC-CM 中舒张增强的基础，排除了 SGLT2、Na+/H+ 交换体、峰值和晚期 Nav1.5 电流以及 L 型 Ca2+电流，但表明 Na+/Ca2+ 交换体的重要作用。事实上，在突变 hiPSC-CM 中的电生理测量表明，SGLT2i 改变了 Na+/Ca2+ 交换电流。
SGLT2i（坎格列净>达格列净>恩格列净）急性增强人类 EHT 的舒张，特别是在 HCM 中，并且在延长培养后增强。SGLT2i 可能代表一种纠正 HCM 早期心脏功能障碍的潜在治疗方法。
